Sex-specific Differences in Emphysema Using a Murine Antisense Oligonucleotide Model of Alpha-1 Antitrypsin Deficiency.

Sex-specific Differences in Emphysema Using a Murine Antisense Oligonucleotide Model of Alpha-1 Antitrypsin Deficiency. Am J Physiol Lung Cell Mol Physiol. 2019 Apr 24;: Authors: Joshi R, Ojha M, Lewis J, Fan Q, Monia B, Guo S, Varisco BM Abstract Alpha-1 antitrypsin (AAT) deficiency is the leading genetic cause of emphysema; however, until recently, no genuine animal models of AAT deficiency existed hampering the development of new therapies. This shortcoming is now addressed by both AAT-null and antisense oligonucleotide mouse models. The goal of this study was to more fully characterize the antisense oligonucleotide model. Both liver AAT mRNA and serum AAT levels were lower in anti-AAT vs. control oligonucleotide treated mice after 6, 12, and 24-weeks. Six and twelve weeks of anti-AAT oligonucleotide therapy induced emphysema that was worse in female than male mice: mean linear intercept 73.4 vs 62.5 (p=0.000003). However, at twenty-four weeks of treatment, control oligonucleotide-treated mice also developed emphysema. After six weeks of therapy, anti-AAT male and female mice demonstrated a similar reduction serum AAT levels and there were no sex or treatment-specific alteration in inflammatory, serine protease, or matrix metalloproteinase mRNAs with the exception of Chymotrypsin-like elastase 1 (Cela1) which was 7 and 9-fold higher in anti-AAT vs. control males and female lungs respectively and 1.6 fold higher in female vs. male ...
Source: Am J Physiol Lung Ce... - Category: Respiratory Medicine Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research